This 12-month project is motivated by the hypothesis that individual differences in initial nicotine sensitivity in humans are associated with nicotine dependence vulnerability and are an important mediator of genetic influences on risk of nicotine dependence. This application combines (1) characterization of existing data on self-report reactions to first cigarette assessed retrospectively in a large adolescent female twin sample (Missouri Adolescent Female Twin Study, MOAFTS) and on subjective reactions to nicotine versus placebo administered by nasal spray to smoking experimenters (smoked fewer than 100 cigarettes lifetime) and measured in the laboratory (Nicotine Challenge Study); and (2) collection of new self-report data on subjective reactions to first cigarette and recalled reactions to nicotine nasal spray in order to assess validity of proposed measures of nicotine sensitivity data and the feasibility of collecting such data from genetically informative samples. If measures can be shown to have acceptable reliability and validity, to be strongly familial and to be associated with nicotine dependence vulnerability, this will lay the groundwork for including such measures in gene-mapping and other genetic studies of nicotine dependence vulnerability and will help identify potential key targets for smoking prevention and intervention. A series of individualized tutorials and formal coursework will provide necessary advanced research training in human behavior genetic of addiction to support this research plan.